Description: The investigator has used in vivo BrdU labeling to show, first, that in young mice, naive and memory T cells have markedly different turnover rates, and second, that in aged mice, these turnover rates are altered in a subset-specific way. The naive and memory subsets of CD4+ and CD8+ cells are defined by their expression of a constellation of markers in normal mice. The ability to discriminate among subsets has been crucial to provide a consistent picture of the alterations associated with aging, since different populations respond differently. Although for the most part, different markers of memory status provide equivalent separations of the cells, there are some indications in this work that additional markers are needed; the majority of memory cells in the aged could represent a phenotypically distinct class from the majority of memory cells in the young. Thus an initial aim will be to screen a number of new potential markers of naive vs. memory cells. The majority of the proposal is focused on identifying mechanisms that could account for the differences in turnover, especially the reduction in turnover of the memory CD4+ cells in the aged. In vivo analyses will assess possible age-related mechanisms by determination of expression of molecules known to control apoptosis in the T cells themselves, measurement of survival-promoting cytokines in serum, and adoptive transfer to determine whether the aged cells undergo increased turnover when transferred to young hosts. In vitro approaches will be used to analyze the ways that the in vivo environment could bring about the observed change in T-cell behavior. Specific cytokines will be tested for their ability to upregulate anti-apoptotic molecules, either directly or through cytokine cascades. The in vitro systems will be used to test for a direct mechanism linking immune response depression with reduced turnover in the aged cells.